ISSN 0145—5680
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`Vol. 47! No. 4 2001
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`LQELLULAR
`AND
`MOLECULAR
`BIOLOGY
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`Editor
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`
`(‘\ Mild“). uh ( 'Ill-UUKHI-Lx
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`HEALTH scn
`ENCES LIBRARY
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`Cellular and
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`Melecular Biologyw
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`Editor-in—Chief
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`
`Institute ofAnatomy 11, Friedrich-Schiller University, Jena, Germany
`
`Associate Editor, USA. and Canada
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`R.F. Ochillo
`
`Graduate School, Morgan State University, Baltimore, Maryland, USA
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`Associate Editor, Asia
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`G. Yamada
`
`C.A.R.D., Kumamoto University, Kumamoto, Japan
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`Associate Editor, Europe
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`K. Konig
`
`Institute ofAnatomy 11, Friedrich—Schiller University, Jena, Germany
`
`Guest Editors
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`P. Bongrand
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`G. Kaplansky
`
`Laboratoire d'Immunologie, INSERM U 387, Marseille, France
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`

`

`CELLULAR AND MOLECULAR BIOLOGYTM‘
`
`2001, Volume 47, Number 4
`
`"-fi‘" HP-H-I “‘-
`
`I Ill
`
`CYTOKINES AND CHEMOKINES
`
`Content
`
`569 Foreword: Cytokines and chemokines
`G. KAPLANSKY and P. BONGRAND
`
`575 Receptor dimerization: a key step in chemokine signaling
`M. MELLADO, A.J. VILA-CORO, C. MARTiNEz-A. and J.M. RODRIGUEZ—FRADE
`
`583
`
`The soluble IL-6 receptors: serum levels and biologicalfunction
`F.A. MONTERO-JULIAN
`
`5 99 Chemokines and lymphocytes: The role ofchemokines and their receptors in the immune system
`H. HASEGAWA and S. FUJITA
`
`609
`
`Interferon—a in inflammation and immunity
`A. KASER and H. TILG
`'
`
`619 TNF and TNFR biology in health and disease
`M.F. MCDERMOTT
`
`637 Role ofinterleukin-13 in innate and adaptive immunity
`J.O. BRUBAKER and L.J. MONTANER
`
`653
`
`The impact of chemokine receptor conformational heterogeneity on HIV infection
`F-. BARIBAUD and R.W. DOMS
`
`661 Mediators ofinflammation and acute phase response in the liver
`K.L. STREETZ, T. WUSTEEELD, C. KLEIN, M.F. MANNS and C. TRAUTWEIN
`
`675 Cytokines in rheumatoid arthritis: Is it all TNF—a?
`P. MIOSSEC
`
`679 Cytokines, from atopy to asthma: The Th2 dogma revisited
`A. MAGNAN, S. BONIFACE, L. MELY, S. ROMANET, E. MAMESSIER and D. VERVLOET
`
`689 Breach ofIL-12 monopoly in the initiation of Type 1 immunity to intracellular infections: IL-12 is not requiredfor host
`defense against viral infections
`Z. XING
`
`695 Pro- versus anti-inflammatory cytokines: myth or reality
`J.-M. CAVAILLON
`
`703 Characterization ofan IL—2 mimetic with therapeutic potential
`R. ECKENBERG, T. ROSE, J.—L. MOREAU, R. WEIL, F. GESBERT, S. DUBOIS, D. TELLO, M. BOSSUS, H. GRAS, A. TARTAR, J. BERTOGLIO,
`S. CHOUAIE, Y. JACQUES, P.M.ALZAR1 and J. THEZE
`
`Indexed/Abstracted in:
`
`Current Contents, Index Medicus, MEDLINE,
`BIOSIS Database, SUBIS,PASCAL/CNRS Database,
`Cam. Sci. Abstn, CAB lnter., Chem. Abstr. Service.
`RIS in References Update
`‘
`published by C.M.B. ASSOCIATION
`Edilarial Cities: 1. Avenue du Pavé Neuf
`F-93160 Noisy-le-Grand (France)
`
`ISSN 01456689
`CMBIDI 47(4) 568'708 (2001)
`Printed by PEETERS — FRANCE S.A.R.L.
`52, Boulevard Saint-Michel
`F-75006 Paris (France)
`
`

`

`
`This material may be protected by Copyright law (Title 17 US, Code)
`
`
`
`
`Cellular and Molecular BiologyTM 47 (4), 695-702
`Printed in France.
`
`0145-5680/01
`2001 Cell. mol. Biol."‘
`
`Review
`
`PRO— versus ANTI-INFLAMMATORY CYTOKINES:
`
`MYTH OR REALITY
`
`Jcan-Marc CAVAILLON
`
`Department of Physiopathology, Institut Pasteur, 28 rue Dr. Roux, 75015 Paris, France
`E—mail.‘jmcavail@pastezuzfr
`
`Received November 8, 2000; Accepted November I 7, 2000
`
`Abstract - Inflammation is characterized by an interplay between pro- and anti-inflammatory cytokines. Cytokines are commonly
`classified in one or the other category: interleukin—1 (IL—1), tumor necrosis factor (TNF), gamma—interferon (IFN—y), IL-12, IL—18
`and granulocyte—macrophage colony stimulating factor are well characterized as pro-inflammatory cytokines whereas IL-4, IL—10,
`IL-l3, IFN—ot and transforming growth factor-[5 are recognized as anti-inflammatory cytokines. In this review, we point out that
`this classification is far too simplistic and we provide numerous examples illustrating that a given cytokine may behave as a pro-
`as well as an anti-inflammatory cytokine. Indeed, the cytokine amount, the nature of the target cell, the nature of the activating
`signal, the nature of produced cytokines, the timing, the sequence of cytokine action and even the experimental model are
`parameters which greatly influence cytokine properties.
`
`Key words: Inflammation, interleukin, chemokine, macrophages, neutrophils, endothelial cells
`
`INTRODUCTION
`
`role during the
`Cytokines play an important
`inflammatory
`process.
`Two
`cytokines,
`namely
`interleukin-1 (IL-1) and tumor necrosis factor (TNF)
`orchestrate the inflammatory response and initiate a
`cascade of mediators which are directly responsible for the
`various events associated with inflammation (e.g.
`increased vascular permeability, chemoattraction of
`circulating leukocytes, proteolysis...). Other cytokines
`such as
`IL—3 and granulocyte-macrophage colony
`stimulating factor (GM-CSF) amplify the release of IL—1
`and TNF, thus favoring the inflammatory process. This is
`also the case for gamma-interferon (lFN—y) the production
`of which is induced by IL-12 and IL—l8. While the
`cytokines mentioned above are classified as
`"pro—
`inflammatory cytokines", 11-4, IL-10, IL-13, interferon-
`alpha (IFN-Ot) and transforming growth factor-[5 (TGF—B)
`are recognized as anti-inflammatory cytokines because of
`their ability to inhibit the release of pro-inflammatory
`cytokines,
`to induce the production of IL-1 receptor
`antagonist (IL-Ira) and the release of soluble TNF
`receptor
`(STNFR) and to limit some of the pro-
`inflammatory activities of IL-1 and TNF. However, the
`events occurring during inflammation are not as simplistic
`
`as an interplay between pro— and anti—inflammatory actors.
`Indeed, they are far more complex ! In this short review
`we will provide some examples which illustrate the fact
`that each of these cytokines ofiers a "half angel — half
`devil" aspect and none can be simply labelled either "pro"
`or "anti".
`
`A TOO SIMPLISTIC DICHOTOMY
`
`Rene’ Magritte, the surrealistic Belgium artist, painted
`a pipe on a picture and wrote "Ceci n’est pas une pipe"
`(This is not apzpe). It is becoming more and more frequent
`to find reports reminiscent ofthis concept: e.g. "TNF is not
`a pro-inflammatory cytokine". For example, in their report
`entitled "TNF is a potent anti-inflammatory cytokine in
`autoimmune—mediated demyelination" Liu et al.
`(42)
`showed that
`in response to injection of myelin
`oligodendrocyte glycoprotein, TNF-deficient mice of
`different genetic backgrounds displayed a multiple
`sclerosis-like disease with a higher incidence, a higher
`mortality, a longer duration and a more severe auto-
`immune disease than their wild type counterparts.
`Similarly, in an experimental model of collagen-induced
`arthritis, it was found that blocking the activity of IEN—y
`(either by anti-IFN—y antiserum or by using IFN—y receptor
`
`695
`
`

`

`696
`
`J.-M. Cavaillon
`
`knock—out mice) resulted in an accelerated onset of the
`disease (70). These results suggested that IFN—y, instead of
`being a pro-inflammatory cytokine, was rather involved in
`counteracting the development of the disease in this
`experimental model. As well, one can assert that "IL-10 is
`not an anti—inflammatory cytokine". Evidence comes from
`in
`viva works
`in which pro-inflammatory
`or
`immunostirnulating activities have been reported for IL-10.
`This is the case for autoimmune diabetes whose onset and
`
`accelerated in transgenic mice
`are
`development
`overexpressing IL-10 in pancreatic islets (52,74). Also, DL—lO
`treatment accelerates allografr rejection of islet cells (77)
`and heart (56). In a model of endotoxin—induced uveitis,
`intra—peritoneal injection of IL-10 potentiated the ocular
`inflammation (59). Finally, in a tumor model, IL-10 was
`reported to favor tumor rejection (6) and using transfected
`mouse mammary adenocarcinoma cells expressing IL-lO,
`Di Carlo et al. (20) showed that the tumor growth area was
`associated with an enhanced level of the chemokine
`
`"monocyte—chemoattractant protein-l" (MCP-l) and of
`inducible nitric oxide synthase (iNOS), an enhanced
`expression ofVCAM-1 and ELAM—l adhesion molecules
`and an enhanced recruitment of leukocytes as compared to
`mice receiving the parent adenocarcinoma. This parallels
`the fact that lL—lO induces E—selectin expression on small
`and large blood—vessel endothelial cells (71).
`We will now review few parameters which influence
`the behavior of the different cytokines and may explain
`why, depending upon the situation, both pro- and anti-
`inflammatory properties can be described for the same
`mediators.
`
`THE AMOUNT OF CYTOKINE
`
`The intensity of the inflammatory response is
`associated with different physiological events which
`correlate with the levels of the produced cytokine. The
`pro—inflammatory cytokines are the most necessary
`mediators to set-up an anti-infectious response; however,
`an exacerbated production of these cytokines may be
`deleterious and even lead to death when used in animal
`
`models and be associated with poor outcome in human
`pathologies such as sepsis. On the other hand, while anti-
`inflamrnatory cytokines are a prerequisite to control the
`cascade of pro—inflammatory mediators, their excessive
`production is associated with a severe immune depression
`as observed in patients following trauma or major surgery.
`Consequently, an increased sensitivity to nosocomial
`infections is observed in these patients.
`The amount of a given cytokine clearly influences its
`
`properties. The best example is given with TGF—[S (9): in
`addition to its role in controlling inflammation, TGF-B
`restrains cell proliferation and controls turnover of the
`extracellular matrix. At high concentration, TGF-B
`suppresses cell proliferation and stimulates the production
`of pathological amounts of extracellular matrix (fibrosis)
`whereas at low levels, TGF-B predisposes to excessive
`cell proliferation, atherogenesis or reduced production of
`extracellular matrix and impaired wound healing.
`Similarly, it has been reported that some effects of TNF
`were influenced by the amount ofthis cytokine used in the
`experimental model. Low doses were found to induced
`angiogenesis whereas high concentrations were associated
`with an inhibition of angiogenesis (23). Moreover, in an
`elegant experimental model of arthritis induced by the
`injection of acidified type II collagen, it was demonstrated
`that
`low amounts of IL—12 were pro-inflammatory
`whereas 100 fold higher amounts were associated with an
`anti—inflammatory process (37). Injection of 5 ng of lL-12
`a day increased the severity of the disease, a property
`which was essentially TNF-dependent whereas treatment
`with 500 ng a day significantly decreased the mean
`arthritis index of the pathology, a phenomenon which was
`essentially IL—lO—dependent.
`Interestingly, only large
`amounts of IL-12 induCed circulating corticosterone.
`
`THE NATURE OF THE TARGET CELL
`
`The anti-inflammatory properties of our quintet of
`anti-inflammatory cytokines have essentially been coined
`with monocytes/macrophages used as target cells. There
`are numerous examples which illustrate that the story
`might be completely different with other target cells. Thus,
`IL—10 was first
`identified and defined as a cytokine
`capable to repress the production of IFN-y by Thl clones
`(25), but more recently it was demonstrated that IL-10
`enhanced the production of IFN-y by NK cells (63),
`increased the intracellular expression of IFN—y and IL-2 in
`CD8+ T-cells in combination with IL—2 afier antigen
`stimulation (60) and increased the number of IL-2
`secreting CD4+ T—cell clones (40). Furthermore, IL—4 and
`IL-10 which inhibit the LPS—induced production of IL—8
`by macrophages, amplify that of endothelial cells (18).
`The different efficiency to inhibit IL-8 production
`depending on the nature of the target cells has also been
`reported for INF-0t which limits this production by LPS-
`activated peripheml blood mononuclear cells and by TNF-a—
`stimulated bone marrow stroma cells but which is
`
`inefficient when acting on LPS-activatedneutrophils (2).
`While IL-l3 diminishes chemokine production by
`
`

`

`Pro— versus anti-inflammatory cytokines
`
`697
`
`activated macrophages, it induces the synthesis of MCP-l
`by endothelial cells (29). While TGF-Bl
`limits the
`production of IL-la and IL—8 in macrophages, it induces
`them in epithelial cells (3 8). While IL-lO can repress the
`production of nitlic oxide (NO) by macrophages 0r
`keratinocytes (4,13), it does not modify NO release by
`mesangial cells (26) and even enhances the production of
`NO by bone marrow derived macrophages and osteoclasts
`(7,65). Acting on bone marrow derived mast cells, IL-lO
`synergized with c-kit ligand and LPS to increase the
`production of cyclooxygenase type 2 and PGD2 as well as
`the expression of E—6 mRNA (51). When addressing the
`regulation of
`IL-lB-induced IL-6 production by
`astrocytes, Pousset et al. (55) showed that IL-10 but
`neither IL—4 nor dexamethasone possessed inhibitory
`properties.
`
`The target cell status may modify its reactivity as well.
`Accordingly,
`IL-lO alone or in synergy with TNF
`enhances HIV replication and TNF production by HIV-
`infected T—cells or promonocytic cells (24,57). Most
`importantly, environmental parameters may also influence
`the reactivity of a given cell type. The best example is
`provided by the study of Pang et a]. (53) who reported in
`chronic bronchial sepsis that IL-10 was able to inhibit the
`LPS—induced TL-8 production by circulating neutrophils
`but was unable to do so when the same assay was
`performed with sputum-derived neutrophils. Similarly,
`analysis of spontaneous NO generation by macrophages
`fiom inflamed, but not normal glomeruli, was down—
`regulated by the addition of IL-4 or TGF-B (22).
`Discrepancies have also been reported in terms of the
`induction of adhesion molecules. For example,
`IL-4
`inhibits the TL—l- or TNF-induced expression of ICAM—1
`and ELAM—l on the surface of endothelial cells, but it
`induces ICAM-l expression in human epithelial cells (64)
`and favors the expression of VCAM-1 on endothelial
`cells, allowing the adherence ofbasophils and eosinophils
`(62). On the other hand,
`IL-lO inhibits ICAM-l
`expression on human Langerhans cells but not on
`keratinocytes, dermal endothelial cells or fibroblasts (12).
`
`THE NATURE OF THE
`
`ACTIVATH‘IG SIGNAL
`
`The inhibitory capacity of the so-called anti-
`inflammatory cytokines may also depend on the nature of
`the triggering agent which acts simultaneously 'on the
`target cell. For example, we have shown that IL—4 and IL-10
`repress the LPS-induced IL-8 production by neutrophils
`while this is not the case when neutrophils Were activated
`
`by TNF-0t (47). Surprisingly, the production of TL-lra by
`activated neutrophils did not reflect what was described
`for the inhibition of IL—8: we reported that IL-10 was not
`acting in synergy with LPS but was active when used
`simultaneously with TNF—0L to fiirther enhance the
`production of IL—lra (46). In contrast, IL-4 amplifies the
`production of IL-lra by neutrophils, independently of the
`nature of the activating signals. The studies on the
`modulation of the production ofvarious chemokines led to
`a rather complex pattern. Thus, it has been reported that
`TL—4 did not aflect the production of RANTES by IFN—y-
`activated human monocytes whereas it was capable to
`increase this production when the cells were activated
`with TNF-0c (44). In the presence of IL-2, the production
`of IFN—y by splenocytes from scid mice was unchanged
`when the cells were cultured with lL-12 and TNF-0t
`
`whereas this production was greatly inhibited when the
`cells were
`activated with
`heat-killed Listeria
`
`monocytogenes (67). When the proliferation of CD8+
`T—cells was monitored in the presence of IL-10,
`the
`proliferative response could be either reduced (in the
`presence of allogenic monocytes), or unchanged (in the
`presence of anti—CD3 antibodies) or even enhanced (in the
`presence of IL-2) (30). Studies on the induction of tissue
`factor on the surface ofmonocytes or endothelial cells also
`revealed major differences based on the nature of the
`activating signal:
`IL—4 and IL-13 fully inhibited the
`induction of the expression of tissue factor on the surface
`of endothelial cells activated with LPS, whereas there was
`
`no inhibition when IL-lB was used as the triggering agent
`(32). A totally different pattern was obtained when tissue
`factor expression was analyzed on the surface of
`monocytes.
`
`THE NATURE OF THE
`
`PRODUCED CYTOKINE
`
`the
`The capacity of a given cytokine to inhibit
`production of others may also vary depending on the
`nature of these other cytokines. For example, TNF was
`surprisingly shown to be a potent inhibitor of IL-12
`secretion from human monocyte—derived macrophages
`activated with either LPS or Staphylococcus aureus
`whereas no similar inhibitory activity was reported when
`addressing the production of IL-la, IL-IB and IL-6 (45).
`Similarly, the so—called anti-inflammatory cytokines do
`not inhibit the production of all cytokines. Thus, IL—lO
`reduces the production of IL-12 by CD40L—activated
`dendritic cells whereas it does not modify the production
`of lL-8 and TNF-0t (l 1). We reported that in whole blood
`
`

`

`698
`
`J.—M. Cavaillon
`
`samples activated by heat—killed Streptococcus pyogenes,
`IL-l3 inhibited the production of IL—8 but was unable to
`modify that of TNF-0t (45). In addition, when the effects
`of IL—4 were studied on monocytes cultured for 7 days, it
`was demonstrated that the LPS—induced IL-1[3 production
`was reduced whereas the TNF—0t production was
`unaffected (31). Studying IL—loL—activated human bone
`marrow stroma cells, IL—4 was also shown to enhance the
`IL-8 production but to inhibit that of leukemia inhibitory
`factor
`(LIF)
`(19). The field of chemokines ofiers
`numerous examples of different regulations induced by
`the same cytokine. For example,
`IL-4 acting on
`macrophages inhibits the production of IL—8 and MIP—la
`but favors the release of MCP—l, RANTES, AMAC-l and
`C10. A completely different profile might be found when
`considering another target cell. Thus, IL—4, when acting on
`endothelial cells favors the production of IL—8 and MCP-l
`but limits that of RANTES. A similar heterogeneity in
`terms of responsiveness has also been reported with lFN—y
`which enhances the production of IP—10 and RANTES by
`macrophages but inhibits the production of GRO, MIP- l or,
`MIP-lB andAlVLAC-l.
`
`THE TIMING
`
`The fact that a mediator exerts an inhibiting or, on the
`contrary, an enhancing effect may also be linked to the
`timing of its exposure to the target cells. For example,
`IL—4 and IL-13 inhibit IL—6,
`IL—12, MCP—l and TNF
`
`production when added simultaneously to activated
`monocytes whereas they enhance the production of these
`cytokines when they are delivered before the activating
`signals (16,36,50). When IL—4 was added simultaneously
`to TNF-0t,
`it had a very low capacity to reduce the
`induction of tissue factor expression on the surface of
`endothelial cells (32). Conversely, a pre—treatment of the
`cells with 11-4 for 8 to 16 hr allowed a significant
`inhibition (48). In an elegant model of resistance to
`systemic Pseudomonas aeruginosa infection, Giampietri
`et al. (28) demonstrated that a 24 hr pre-treatment of mice
`with IL—4 was protective when high number of CFU were
`injected whereas when injected only 1 hr before the
`bacterial challenge with a lower number of CFU, IL—4 was
`deleterious.
`In the first case enhanced survival was
`
`associated with a reduced level of circulating TNF while
`in the later one reduced survival was associated with an
`
`enhanced level of circulating TNF. Another fascinating
`example of timing is provided by the efi‘ect of cortisol
`infiJsion in human volunteers. While an injection of LPS
`at the end of the cortisol infusion did not lead to detectable
`
`circulating TNF, the same injection made 12 to 144 hr
`after the infusion led to far higher levels of TNF and IL—6
`than those reached in the same volunteers who did not
`
`receive the cortisol pre—treatment (3).
`
`THE SEQUENCE OF CYTOKINE ACTION
`
`Cytokines are the words of a universal language 'used
`by cells. As in any language, the order of the words
`influenCes the meaning of the sentence. Accordingly, the
`sequence of exposure to cytokines plays a key role in the
`nature of the signals delivered to the cells. For example,
`TNF and INF-y used simultaneously have no significant
`effect on the production of NO by rat bone marrow-
`derived macrophages. In contrast, IFN—y primes the cells
`which then produce significant amounts of NO when
`exposed to TNF. Most interestingly, if the cells are first
`exposed to TNF, then 4 hrs later to IFN—y and afier an
`additional 4 hrs finally exposed to TNF,
`they do not
`produce any NO (21). The same desensitization was
`observed with a pre-treatment with IL-4 or TGF-B
`whereas IL—lO had no inhibitory activity in this model. A
`similar observation has been made when the LPS—induced
`
`production of IL-12p70 was investigated (33): cells pre-
`exposed to IFN— , produced significant amounts of lL-l2
`whereas low or no production was obtained with cells pre-
`treated with either TNF or TNF + lFN-y.
`
`THE EXPERINIENTAL MODEL
`
`We have studied in vitro the effect of IL-10 pre-
`treatment on the production of TNF and IL—6 by
`leukocytes upon stimulation by LPS. We reported that in
`the presence of IL-10,
`the prevention of monocyte
`adherence by red cells in the whole—blood assays or by
`cultures of peripheral blood mononuclear cells on
`Teflon®, allowed a higher cytokine production as
`compared to cells maintained in culture medium alone
`before the LPS activation. When the first step of the
`experiment was performed on plastic (i.e. with adherence
`of monocytes) the classical inhibitory activity of IL—10
`was found (1 ). Altogether, these results indicate that IL-10-
`induced modulation of cytokine production depends on
`the in vitro experimental procedures. More recently, a
`similar "pro-inflammatory" activity of IL-10 was
`reported in human volunteers receiving an LPS injection
`(39). The use of different in vivo models may result in
`completely opposite conclusions. Indeed, in a model of
`immune complex-induced acute lung injury it was
`reported that the neutralization of IL-13 increased the
`
`

`

`Pro- versus anti—inflammatory cytokines
`
`699
`
`inflammatory process, suggesting that endogenous IL-13
`restrained inflammation (41). In contrast, transgenic mice
`over-expressing IL—13
`in the
`lungs
`showed an
`inflammatory mononuclear infiltrate, eosinophils around
`airways and in parenchyma, an airway epithelial
`hypertrophy, a goblet cell hyperplasia, a hyperproduction
`of mucus and a selective local production of the eotaxin
`chemokine (78). This last paper is reminiscent of the
`inflammatory role of IL-13 demonstrated in various
`models of asthma (73).
`We already mentioned the protective role of IFN—y in a
`model of collagen-induced arthritis and the accelerated
`onset of the disease in IFN-y-KO mice (70). Billiau’s
`group further demonstrated that this observation was only
`true when collagen was injected together with complete
`Freund adjuvant (CFA). Indeed, when incomplete Freund
`adjuvant was employed, the disease did not occur in the
`IFN—y receptor knock-out animals (49). The authors
`demonstrated that on one hand IFN—y induced pro-
`inflammatory cytokines such as TNF and IL—12, on the
`other hand,
`in the model using CFA (i.e. associating
`Mycobacteria), IFN-y had a beneficial role by restraining
`both the expansion of hematopoietic process and the
`number of macrophages, a major source of pro—
`inflammatory cytokines.
`
`IL-6, THE PARADIGM OF AMBIGUITY!
`
`Acute phase proteins are essentially protective and
`limit
`the inflammatory process. They possess anti-
`protease and some scavenger activities. Accordingly, IL-6
`can be considered as an anti-inflammatory cytokines
`thanks to its potency to induce the release of acute phase
`proteins by hepatocytes, including IL—lra (27). It was also
`mentioned that 1L-6 inhibited therelease of IL-1 and TNF
`
`(61) and féVored that of soluble TNF receptor (66).
`Accordingly, numerous experimental models, including
`systemic or
`local endotoxemia demonstrated the
`
`protective activity of IL-6 (75,76). However, in contrast,
`IL-6 can induce bone resorption (34), muscle atrophy
`(68), anemia (35) and can prime neutrophils for the
`production of PAF and superoxide anion (8,10). While 1L—6
`doesi not activate endothelial cells, it induces MCP-l, -3
`and IL—8 production, STAT—3 activation, and ICAM-1
`expression, in the presence of its soluble receptor which is
`naturally found in plasma (58). Deleterious activities of
`IL-6 in vivo have been suggested by experimental models
`of ischemia reperfusion and of lung injury performed in
`IL—6 knock-out mice which were shown to exhibit lower
`
`inflammatory responses (14,15).
`
`CONCLUSION
`
`We have to admit that dogma often result from an over—
`simplification of the described phenomena. Accordingly,
`dogma are made to be broken!
`It appears that
`the
`inflammatory response is an extremely complex interplay
`of mediators whose exact contribution may depend on
`many influencing parameters. Finally,
`to add to the
`complexity, one should not forget that humans are not
`equal
`in terms of their inflammatory responses. The
`known genetic polymorphisms for many pro- as well as
`anti-inflammatory cytokines (17,54,69,72) are associated
`with the amplitude of the inflammatory process.
`In
`addition, another polymorphism exists in terms of target
`cell reactivity in response to cytokine signaling (5). This
`individual heterogeneity has also to be considered when
`addressing the inflammatory response.
`
`REFERENCES
`
`1. Adib-Conquy, M., Petit, A.—F., Marie, C., Fitting, C. and Cavaillon,
`J.-M., Paradoxical priming elfects ofIL—10 on cytokine production.
`Inm. Immunol. 1999, 11: 689—698.
`2. Aman, M.J., Rudolf, G., Goldschmitt, J., Aulitzky, W.E., Lam, C.,
`Huber, C. and Peschel, C., Type—I interferons are potent inhibitors
`of interleukin—8 production in hematopoietic and bone marrow
`stromal cells. Blood 1993, 82: 2371—2378.
`3. Barber, A.E., Coyle, S.M., Marano, M.A., Fischer, E., Calvano,
`S.B., Fong, Y., Moldawer, LL. and Lowry, S.F. Glucocorticoid
`therapy alters hormonal and cytokine responses to endotoxin in
`man. J. Innmmol. 1993, 150: 1999-2006.
`4. Becherel, P.A., Le Goff, L., Ktorza, S., Ouaaz, F., Mencia—Huerta,
`J.M., Dugas, B., Debre, P., Mossalayi, MD. and Arock, M.,
`Interleukin-10 inhibits
`IgE-mediated nitric oxide synthase
`induction and cytokine synthesis in normal human keratinocytes.
`Em: J. Immunol. 1995, 25: 2992-2995.
`5. Bender, J.R., Sadeghi, M.M., Watson, 0, Pfau, S. and Pardi, R.,
`Heterogeneous activation thresholds to cytokines in genetically
`distinct endothelial cells: evidence for diverse transcriptional
`responses. Pmc. Natl. Acad. Sci. USA 1994, 91: 3994-3998.
`6. Bennan, R.M., Suzuki, T., Tahara, H., Robbins, P.D., Narula, S.K.
`and Lotze, M.T., Systemic administration of cellular IL—lO induces
`an effective specific and long-lived immune response against
`established tumor in mice. J. Immunol. 1996, 157: 231—238.
`7. Betz—Corradin, S.B., Fasel, N., Buchmuller—Rouiller, Y., Ransijn,
`A., Smith, J. and Mauel, J., Induction of macrophage nitric oxide
`production by interferon—gamma and tumor necrosis factor—alpha is
`enhanced by interleukin—10.Ezu: J. Immunol. 1993, 23: 2045—2048.
`8. Biffl, W.L., Moore, BB, Moore, EA, Barnett, C.C., Silliman, CC.
`and Peterson, V.M., Interleukin-6 stimulates neutrophil production
`of platelet activatiing factor. J. Leuk. Biol. 1996, 59: 569—574.
`9. Border, WA. and Noble, N.A., Targeting TGF—beta for treatment
`of disease. Nat. Med. 1995, 1: 1000-1001.
`10. Borish, L., Rosenbaum, R., Albury, L. and Clark, 8., Activation of
`neutrophils by recOmbinant
`interleukin-6. Cell Immzmol. 1989,
`121: 280-289.
`11. Buelens, C., De Groote, D., Goldman, M. and Willems, F.,
`Differential effects of interleukin-10 on the production of
`interleukin-12 and interleukin-8 by human dendritic cells
`
`

`

`700
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`J.—M. Cavaillon
`
`generated from peripheral blood. Transpl. Proc. 1996, 28: 3255—
`3256.
`Chatelain, R., Wollenberg, A., Martin, C., Panhan—Gross, A.,
`Bieber, T., Degitz, K. and Heckmann, M., IL—lO inhibits ICAM-l
`expression on human Langerhans cells but not on keratinocytes,
`dermal endothelial cells or fibroblasts. Arch. Dermalol. Res. 1998,
`290: 477-482.
`
`Cunha, F.Q., Moncada, S. and Liew, F.Y., Interleukin—10 (IL—10)
`inhibits the induction of nitric oxide synthase by interferon-gamma
`in murine macrophages. Biochem. Biophys. Res. Commrm. 1992,
`182. 1155- 1159
`Cuzzocrea, S, De Sarro, G., Costantino, G. Ciliberto, G., Mazzon,
`E. De Sarro, A. and Caputti, A..P, IL—6 knock—out mice exhibit
`resistance to splanchnic artery occlusion shock. J. Leuk. Biol.
`1999a, 66: 471-480.
`Cuzzocrea, S., Sautebin, L., De Sarro, G., Costantino, G.,
`Rombola, L., Mazzon, E., Ialenti, A., De Sarro, A., Ciliberto, G., Di
`Rosa, M., Caputti, A. P. and Thiemennann, C., Role of IL—6 in the
`pleurisy and lung injury caused by carrageeenan. J. Immzmol.
`1999b, 163: 5094-5104.
`D’Andrea, A., Ma, X., Aste—Amezaga, M., Paganin, C. and
`Trinchieri, G., Stimulatory and inhibitory effects of interleukin
`(IL)-4 and IL-13 on the production of cytokines by human
`peripheral blood mononuclear cells: priming for IL—12 and tumor
`necrosis factor alpha production. J. Exp. Med. 1995, 181: 537—546.
`Danis, V.A., Millington, M., Hyland, V.J. and Grennan, D.,
`Cytokine production by normal human monocytes: inter—subject
`variation and relationship to an IL-1 receptor antagonist (IL-1Ra)
`gene polymorphism. Clin. Esp. Immzmol. 1995, 99: 303—310.
`De Beaux, A.C., Maingay, J.P., Ross, J.A., Fearon, KC. and Carter,
`D.C.,
`Interleukin-4 and interleukin—10 increase endotoxin-
`stimulated human umbilical vein endothelial cell
`interleukin-8
`release. J. Inle/f. Cyto. Res. 1995, 15: 441-445.
`Denizot, Y., Besse, A., Raher, S., Nachat, R., Trimoreau, F.,
`Praloran, V. and Godard, A., Interleukin-4 (IL-4), but not IL-10,
`regulates the synthesis of IL-6, IL-8 and leukemia inhibitory factor
`by human bone marrow stromal cells. Biochim. Biopliys. Acla
`1999, 1449: 83-92.
`Di Carlo, E., Coletti, A., Modesti, A., Giovarelli, M., Fomi, G. and
`Musiani, P., Local release of interleukin-10 by transfected mouse
`adenocarcinoma cells exhibits pro- and anti-inflammatory activity
`and results in a delayed tumor rejection. Eur. Cylola'ne Netw. 1998,
`9: 61—68.
`
`Erwig, L.-P., Kluth, D.C., Walsh, GM. and Rees, A.J., Initial
`cytokine exposure determines function of macrophages and
`renders them unresponsive to other cytokines. J. Inmnmol. 1998,
`161: 1983-1988.
`
`Erwig, L.P., Stewart, K. and Rees, A.J., Macrophage from inflamed
`but not normal glomeruli are unresponsive to anti—inflammatory
`cytokines. Am. J. Palliol. 2000, 156: 295-301.
`Fajardo, L.F., Kwan, H.H., Kowalski, J., Prionas, SD. and Allison,
`A.C., Dual role of tumor necrosis factor-a in angiogenesis. Am. J.
`Pat/ml. 1992, 140: 539-544.
`Finnegan, A., Roebuck, K.A., Nakai, B.E., Gu, D.S., Rabbi, M.F.,
`Song, S. and Landay, A.L., IL-10 cooperates with TNF-or to
`activate HIV-l
`from latently and acutely infected cells of
`monocyte/macrophage lineage. J. Immzmol. 1996, 156: 841-851.
`Fiorentino, D.F., Bond, M.W. and Mosmann, T.R., Two types of
`mouse T helper cell. IV. Th2 clones secrete a factor that inhibits
`cytokine production by 1111 clones. J. Exp. Med. 1989, 170: 2081—
`2095.
`
`Fouqueray, B., Boutard, V., Philippe, C., Komreich, A., Marchant,
`A., Perez, J., Goldman, M. and Baud, L., Mesangial cell-derived
`interleukin—10 modulates mesangial
`cell
`response
`to
`lipopolysaccharide. Am. J Poi/101. 1995, 147: 176—182.
`
`27.
`
`28.
`
`29.
`
`30.
`
`31.
`
`32.
`
`33.
`
`34.
`
`35.
`
`36.
`
`37.
`
`38.
`
`39.
`
`40.
`
`41.
`
`42.
`
`Gabay, C., Smith, M.F., Eidlen, D. and Arend, W.P., Interleukin—1
`receptor antagonist is an acute phase protein. J. Clin. Invest. 1997,
`99: 2930-2940.
`
`Giampietri, A., Grohmann, U., Vacca, C., Fioretti, M.C., Puccetti,
`P. and Campanile, F., Dual effect of IL—4 on resistance to systemic
`Gram-negative infection and production ofTNF-ot. Cytokine 2000,
`12: 417-421.
`Goebeler, M., Schnarr, B., Toksoy, A., Kunz, M., Brocker, E.-B.,
`Duschl, A. and Gillitzer, R., Interleukin-13 selectively induces
`monocyte chemoattractant protein—1 synthesis and secretion by
`human endothelial cells.
`Involvement of IL-lRa and Stat-6
`
`phosphorylation. Immunology 1997, 91: 450—457.
`Groux, H., Bigler, M., de Vries, J.E. and Roncarolo, M.G.,
`Inhibitory and stimulatory effects of IL-10 on human CD8+ T—cells.
`J. Immzmol. 1998, 160: 3188-3193.
`Hart, P.H., Jones, CA. and Finlay—Jones, J.J., Monocytes cultured
`in cytokine—defmed environments differ fiom freshly isolated
`monocytes in their responses to IL-4 and IL-10. J. Leukoc.